S-substituted 2-thioadenosine-5{40 -monophosphates and process for producing the same

ABSTRACT

Novel S-substituted 2-thioadenosine-5&#39;&#39;-monophosphate and the salt thereof which are useful as a coronary vascular vasodilator and an aggregation inhibitor for blood platelets and a process for producing an S-substituted 2-thioadenosine-5&#39;&#39;-monophosphate and the salt thereof by phosphorylation of an S-substituted 2thioadenosine are disclosed.

United States Patent [1 1 Kikugawa et a1.

1 1 S-SUBSTITUTED Z-THIOADENOSIN E-S -MONOPHOSPHATES AND PROCESS FORPRODUCING THE SAME [751 Inventors: Kiyomi Kikugawa; Hideo Suehiro,

both of Kokubunji; Motonobu lchino; Tokuro Nakamura, both of Mitaka. allof Japan [73] Assignee: Kohjin Co.. Ltd., Tokyo, Japan [22] Filed: July10, 1973 [21] Appl. No.: 378,116

[30] Foreign Application Priority Data Dec. 26. 1972 Japan 47429619 Dec.26. 1972 Japan 47-129620 Mar. 12.1973 Japan 48-27985 Mar. 23. 1973 Japan48-32703 [5 US. Cl t. 260/2115 R; 424/180 [51] Int. Cl. CO'IH 19/20 [58Field of Search 260/2115 R 1 1 Nov. 11, 1975 [561 References CitedUNITED STATES PATENTS 3.380.996 4/1968 Honjo ct al. 2611/21 1.5 R3.413.282 11/1968 Yushikawa ct a1 260/2115 R 3.444.158 5/1969 HOHJU cta1. 260/2115 R 3.464.973 9/1969 Ouchi ct a1. 260/2115 R 3.466273 9/1969Soua ct a1 260/2115 R 3.703.507 11/1972 Haskell et a1v 260/2115 R3.752.804 8/1973 lmai et a1 260/2115 R 3.781.274 12/1973 Maguire et a12611/2115 R Primar E.\'mnmw-Johnnie R. Brown Attorney, Age/1!, orFirmsughrue. Rothwell. Mion. Zinn & Macpeak [57] ABSTRACT NovelS-substituted Z-thioadenosinc-S monophosphate and the salt thereof whichare useful as a coronary vascular vasodilator and an aggregationinhibitor for blood platelets and a process for producing anS-substituted 2-thioadenosine-5'- monophosphate and the salt thereof byph0sphorylation of an S-substituted 2-thioadenosine are disclosed.

18 Claims. N0 Drawings S-SUBSTITUTED Z-THIOADENOSINE-S '-MONOPHOSPHATESAND PROCESS FOR PRODUCING THE SAME BACKGROUND OF THE INVENTION l, Fieldof the Invention The present invention relates to a novel S-substituted2-thioadenosine-5'-monophosphate and the salt thereof and to a processfor producing the same by acting a phosphorylating agent on anS-substituted 2-thioadenosine. It also relates to a coronary vascularvasodilator and an aggregation inhibitor for blood platelets comprisingthe above-described compounds.

2. Description of the Prior Art Michael et al have already found thatZ-methylthioadenosine-S-monophosphate shows an aggregation inhibitionactivity on blood platelets with small toxicity (Nature," vol. 222, p1073, 1969; British Pat. No. l,226,699; and U.S. Pat. No. 3,678,162).

However, this compound does not provide a sufficient aggregationinhibition activity on blood platelets.

SUMMARY OF THE INVENTION As a result of extensive investigations todevelop an adenosine-5 -monophosphate derivative useful as a remedy forthrombosis and as an aggregation inhibitor for blood platelets, theinventors have discovered novel S-substitutedZ-thioadenosine-S'-monophosphates and the salt thereof byphosphorylating a hydroxy group located at the 5'-position of anS-substituted 2-thioadenosine. The object of the present invention is toprovide the above-described compounds, a process effective for producingthe compounds and a useful coronary vascular vasodilator and anaggregation inhibitor for blood platelets.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates toan S-substituted 2- thioadenosine-5'-monophosphates represented by thefollowing general formula;

H2O5POCH2 OH OH and the salt thereof, wherein R represents a primary orsecondary alkyl group having five to carbon atoms, a cycloalkyl grouphaving five to 10 carbon atoms, a cycloalkylmethyl group, a benzylgroup, a p-substituted benzyl group, an allyl group, or a B- ory-suhstituted allyl group.

As the alkyl group having five to 10 carbon atoms, there are illustratedan n-amyl group, an iso-amyl group, a n-hexyl group, a n-heptyl group, an-octyl group, a n-nonyl group, a n-decyl group, a 2-ethyl-n hexylgroup, and the like. As the cycloalkyl group, there are a cyclopentylgroup, a cyclohexyl group, a cy- 2 cloheptyl group, and the like As thecycloalkylmethyl group, those having live to 10 carbon atoms, inparticular cyclohexylmethyl, etc.. are preferable. As the p-substitutedbenzyl group, there are a p-chlorobenzyl 2 group, a p-nitrobenzyl group,etc. and, as the [3- or ysubstituted allyl group, there are atrans-crotyl group. a B-methallyl group, and the like.

S-substituted 2-thioadenosine-5'-monophosphates are produced byphosphorylating a hydroxy group located at 5'-position of acorresponding S-substituted Z-thioadenosine.

In the process of the invention, a phosphorylating agent may be acted onthe starting material in which hydroxy groups at 2'- and 3-positionsthereof are protected with commonly employed protectives such as acetyl,benzoyl, isopropylidene, etc. Or else. a hydroxy group at S-position mayselectively be phosphorylated by acting, under suitable reactionconditions, a phosphorylating agent on the starting material in whichhy' droxy groups as 2'- and 3'-positions are not protected.

As the phosphorylating agent to be applied to a S- substituted2thioadenosine whose hydroxy groups at 2'- and 3'-positions areprotected, phosphorus oxychloride, phosphorus pentachloride, partiallyhydrated phosphorus oxychloride, pyrophosphoryl chloride, or the like isused in the presence or absence of a suitable organic solvent accordingto the phosphorylating method usually practiced for nucleoside.

Also, a hydroxy group at 5'-position of a S-substituted Z-thioadenosinewhose hydroxy groups at 2'- and 3'-positions are not protected mayselectively be phosphorylated. That is, a hydroxy group at 5'-positionof the starting material wherein hydroxy groups at 2'- and 3-positionsare not protected may selectively and quantitatively be phosphorylatedby acting phosphorus oxychloride, partially hydrated phosphorusoxychloride, phosphorus pentachloride or pyrophosphoryl chloride on thestarting material in the presence or absence of an organic solvent suchas m-cresol, acetonitrile, triethyl phosphate, ethyl acetate, pyridine,or the like.

In the present invention, the phosphorylating agent is used in an amountequimolar to the starting material or more than that and, suitably in anamount 2 10 times the equimolar amount. The reaction is in generalconducted at about 25C to about +30C for l 10 hours. The thus obtainedreaction product is converted to a 5'-phosphate derivative by addingthereto ice-water to hydrolyze. Where the thus hydrolyzed product is a2',- 3'-isopropylidene derivative, the isopropylidene group may beremoved by, e.g., hydrolyzing at 60C for 1 hour at pH 2, whereas wherethe hydrolyzed product is a 2',3'-di-O-acetyl derivative, the acetylgroups may be removed by, eg, hydrolyzing at 37C for 24 hours at pH 10.The thus obtained S-substituted Z-thioadenosine-5-monophosphate may becollected as a H type compound or as a pharmacologically acceptable saltsuch as Li salt-type, 2Li salt-type, Na salt-type, ZNa salt-type, Ksalt-type, 2K salt-type, NH, salt-type, ZNH, salt-type, Ba salt-typecompound, or the likev S-substituted 2-thioadenosine-5'-monophosphatesobtained by the present invention showed 30 inhibition of adenosine-Sdiphosphatet l0M)-induced aggregation of blood platelet suspensionaccording to the method of Born and Cross (Journal of Physiology," vol.168, p. 178, 1963) using a suspension con taining platelets of human orrabbit at a level of lO""M as shown in the following example in theTable II. This inhibition activity does not dissipate but lasts evenwhen treated in plasma at 37C for 120 minutes. The compounds of thepresent invention show far stronger aggregation inhibition activity onblood platelets as compared with the homologous compound. 2-methy1-thioadenosine-S'-monophosphate. Therefore. the compounds of theinvention are of extremely great utility value as a medicine.

The starting S-substituted 2-thioadenosine may be prepared by reactingZ-thioadenosine with a halogenated hydrocarbon, by reaction anS-substituted 2-thio- 6-benzoyladenine with 2,3,5tri-O-acyl-,B-D-ribofuranosyl halide, or by reacting an S-substituted 2-thio-6-chloropurine with tetra-O-acetylribofuranose, as described inJapanese Pat. Application Nos. 60464/72; 57366/72; 59423/72; 59422/72and 57365/72.

The process for producing S-substituted Z-thioadenosines is illustratedbelow.

REFERENCE EXAMPLE 1 2-Benzylthioadenosine R, value in paperchromatography (sohent: n-butunol/watcr 84:16) 073 UV: Arnax (pH 1]272.5 mp (51 17000) Amax (pH 7) 235 my (1 24100) 278 mp (E: 16000) ltmax(pH 13) 234 my. (e: 24600) 278 my. (s: 16000) Elementary Analysis:

Calcd. for C -H O N S. /H O. /C H -,OH: C, 51.29; H. 5.49; N, 16.61; S.7.60 Found: C, 5 1.40; H, 5.52; N. 16.73; S, 7.45 7:.

REFERENCE EXAMPLE 2 Z-Benzylthioadenosine 10 m moles of2-benzylthio-fi-benzoyladenine was added to 50 m1 of a 50% ethanol, and10 m moles of corrosive sublimate was added thereto. Upon adding thereto0.4 ml of a 10% sodium hydroxide solution, there was obtained a HgClsalt of 2-benzylthio-6-benzoyladenine as a precipitate. The thus formedprecipi tate was filtered, dried and added to 200 ml of anhydrousxylene. Thereafter, 100 ml of a xylene solution containing 12 m moles of2,3,S-tri-O-benzoyl-B-D- ribofuranosyl bromide was gradually addedthereto and the mixture was refluxed for 3 hours. Then, the resultingfiltrate was concentrated, dissolved in chloroform. washed with a 30%potassium iodide solution then with water, dried and concentrated todryness. To the residue was added 100 ml of an absolute methanolcontaining ammonia and, after treating for 2 days at 0C, concentrated,followed by adding thereto ethanol to obtain a crystalline product.Recrystallization from water ethanol-yielded 2.52 g (60% yield) of thedesired product having a melting point of 152 154C.

R, value in paper chromatography (solvent: n-butanol/watcr 84:16) 0.73UV: )tmax (pH 1] 272.5 my. (5: 17000) )rmax (pH 7) 235 my. (6: 24100)278 mp (e: 16000) Amax (pH 13) 234 my. (:1 24600) 278 mu (6: 16000)Elementary analysis:

Calcd. for C H O N S.%H O.%C H OH: C, 51.29; H, 5.49; N, 16.61; S, 7.60Found: C, 51.30; H, 5.71; N. 16.71; S. 7.34

REFERENCE EXAMPLE 3 2( -n-Amylthio)adenosine UV: Amax (pH 1) 272 my Amax(pH 7) 237 mp.. 278 mp Amax (pH 13) 236 mp. 279 my.

Elementary analysis:

Calcd. for C, H O ,N S: C, 48.76; H, 6.27; N, 18.95 Found: C, 48.65; H,6.21; N, 19.08

The present invention will now be described in greater detail by thefollowing examples of the preferred embodiments of the invention, butthey are not to be construed as limiting the scope of this invention.

EXAMPLE 1 0.739 Gram (2 m moles) of 2-isoamylthioadenosine was dispersedin a mixture of 2 ml of acetonitrile and 0.78 ml of pyridine, and 0.816ml (8.8 m moles) of phosphorus oxychloride was added thereto undercooling. Then, 0.072 ml (4 m moles) of water was added thereto and thereaction was conducted for 6 hours. The reaction was discontinued byadding ice-water to the reaction mixture and, after hydrolysis, thehydrolyzed solution was adsorbed on 20 g of active carbon. After washingwith water, the active carbon column was subjected to elution with 800ml of a 10% ammonia-ethanol (1:1) and the resulting eluate wasconcentrated to dryness. The residue was fractionated and purified on acellulose column 1.7 X 40 cm) by eluting with a solvent ofnpropanol-ammonia-water (20: 10:3 The precipitated formed by adding anethanol solution of barium iodide was collected by centrifugation. Afterrepeated purification from water-ethanol, there was obtained2-isoamylthioadenosine-5 '-monophosphate barium salt in yield.

UV: Amax (pH 1) 273 my. (s,,: 14000) R, value in paper chromatography1000 V; 1 hour: control S'-AMP: +4.7 cm) mono spot Inorganic phosphoricacid was released in 100% yield when the product was treated with5'-nucleotidase of EXAMPLE 2 0.779 Gram (2 m moles) of2',3'-O-isopropylidene- 2-isoamylthioadenosine was cooled in a dryice-acetone bath, and 1.5 g (6 m moles) of pyrophosphoryl chloride wasadded thereto. The resulting mixture was warmed to C and stirring wascontinued for 4 hours. Thereafter, the mixture was again cooled in thedry-iceacetone bath and 1.5 ml of water was added thereto. Then, themixture was again warmed to 20C, and 50 ml of water was added theretofollowed by stirring for 5 hours at 20C. To the solution was then added1M ammonium hydroxide solution to adjust the pH to 8.5. The precipitateformed was filtered off and the filtrate was concentrated. The resultingconcentrate was placed on a cellulose column and eluted with a solventof npropanol-ammonia-water (20:l0:3). Fractions containing the desiredproduct was collected and concentrated to dryness. Upon adding acetoneto the residue, there was obtained a crude powder which was thenreprccipitated using methanol-acetone to give 2-isoamylthioadenosine-S'-monophosphate ammonium salt in 60% yield.

The thus obtained power exhibited quite the same activity to an enzymeas that of the product obtained in Example 1.

EXAMPLE 3 370 mg (1 m mole) of 2-n-amylthioadenosine was suspended in amixture of 1 ml of acetonitrile and 0.39 ml of pyridine, and 0.408 ml(4.4 m moles) of phosphorus oxychloride was added thereto under cooling.Then, 0.036 ml (2m moles) of water was added thereto and the reactionwas conducted for 6 hours. lcewater was added to the reaction mixture todiscontinue the reaction, and the precipitate formed was collected bycentrifugation. A preparative paper chromatography was conducted usingas a solvent isopropanolammonia-water (711:2) and fractions whose R,value was 0.50 were collected and concentrated. The resultingconcentrate was dissolved in 1 ml of water and hydrochloric acid wasadded to the solution to form a precipitate. The thus formed precipitatewas collected by centrifugation, washed with water and dried to give 2-n-amylthio-adenosine-S'-monophosphate in 90% yield.

UV: Amax (pH 1) 273 my. (1,: 14000) Amax (pH 7) 236 mp (c,,: 20000) Amax(pH 13) 236 mp 20500) 278 mp. (e,,: 139001 R, value in paperchromatography (solvent: isopropanol/ammonia/water 0.50 7:1:2) mono spotMigration in electrophoresis: (pH 7.5;

6 Elementary analysis:

Calcd. for C ,-,H O;N ,SP.2H O; C, 38.38; H. 6.01: N. 14.92; P. 6.60%.Found: C, 38.40; H. 6.28; N. 14.75; P. 6.71%.

EXAMPLE 4 0.752 Gram (2m moles) of 2-allylthioadenosine was suspended ina mixture of 2 ml of acetonitrile and 0.78 ml of pyridine, and 0.816 ml(8.8 m moles) of phosphorus oxychloride was added thereto under cooling.Then, 0.072 ml (4 m moles) of water was added thereto, and the reactionwas conducted for 6 hours. lee-water was added thereto to discontinuethe reaction and hydrolyze. The resulting hydrolyzed solution was thenadsorbed on 20 g of active carbon and washed with water. The activecarbon column was subjected to elution with 800 ml of 10% aqueousammonia-ethanol 1:1 and the eluate was concentrated to dryness. Theresulting residue was then placed on a cellulose column 1.7 X 40 cm) andeluted with a solvent of isopropanolammonia-water (7: l :2). Fractionshaving a R, value of 3.2 as determined by paper chromatography in thesame solvent system were pooled and concentrated. To the concentrate wasadded an ethanolic solution of barium iodide, and the precipitate formedwas collected by centrifugation. After repeating precipitation withwater-ethanol, there was obtained 1.00 g (about yield) ofZ-aIlyIthio-adenosine-S'-monophosphate bar ium salt.

Migration in electrophoresis:

(pH 7.5; 0.05 phosphate buffer: 1000 V; +6.7 cm

1 hour: control: 5'-adeny1ic acid.

Release of inorganic phosphoric acid by 104 mole Z 5'nuclcotidase of(rolalus Atrox Venom Content of inorganic phosphoric acid 0 mole 9Elementary analysis:

Calcd. for C, l-l, O N SP.Ba.2H O: C, 26.43; H, 3.41; N, 11.86 Found: C,26.69; H, 3.23; N, 11.70

EXAMPLE 5 0.844 Gram of 2-benzylthioadenosine was suspended in a mixtureof 2 ml of acetonitrile and 0.78 ml of pyridine. Then, 0.816 g (8.8 mmoles) of phosphorus oxychloride was gradually added thereto understirring in an ice water bath. Thereafter, 0.072 ml (4 m moles) of waterwas added thereto and the reaction was conducted for 6 hours. lee-Waterwas added to the reaction mixture to discontinue the reaction and theprecipitate formed upon hydrolysis was collected by centrifugation. Thethus formed precipitate was placed on a cellulose column (1.7 X 40 em)and eluted with a solvent of isopropanol-ammonia-water (7:1 :2).Fractions having a R, value of 0.34 as determined by paperchromatography in the same solvent system were pooled and concentrated.To the concentrate was added an Table 2 cthanolic solution of bariumiodide. and the precipitate lnhihimm Ur Amdnduccd pmclfl flggmgmkmformed was collected by centrifugation. After washing S-substitutcdZ-Ihiotldcnosinc 5'-munnphosphzltcs with ethanol. there was obtained1.08 g (about 9(l7r i R 'g I 1 a It uman yield) of benzylthioadenosme 5monophosphate SOL Molar .5 Mmm barium salt. Compound \cnt concri ADP!ADP) 2-nbarium DM- I0 83 Amylthio salt 50* UV Amen IpH I) 273 mg (q.1390!]! AMP ammo- Amax (H 0) 234 mp. (c,,: 20100) 10 nium saline 08x1080 278 my (6,,: 13-1-00) salt 0.8Xl0 54 84 Amax (pH 13] 278 mu (6,:13700) 0.KX|0" 22 54 R, \aluc in paper chromatography 2- tsohcnt:isopropanol/ammonia/watcr 0.34 Allylthio barium DMSO 10 82 7: I 2) AMPSalt Migration in electrophoresis: ammo- (pH 7.5; 0.05M phosphatebuffer; +1.5 cm l5 nium saline 03x10 80 1000 V. l houri control:5'-a|dcnylic salt acid. +2.0 cm) 0.9Xl0" 59 86 Release of inorganicphosphoric acid by 96 mole /1 0.9 l0" 37 31 5'-nuclcotidasc of CrotalusAtrox Venom AMP Content of inorganic phosphoric acid: 2.5 mole 71disodium salinc I0 52 salt 10' 35 10 5 Elementary analysis: Adenvsinv DM66 u 4 Calcd. for c u om spaazii o; c, 31.86; H, 13-. Z, 943.46;N,10.93;P. 4.83 7c. Found: C. 31.88; H, 3.1 l; N, 10-" 37 4! l LOO.25 'DMSO=Dimelh \lsulfnxidc "AMP=Adcnosine S '-n1onophosphatc EXAMPLE 6The compounds listed in Table 1 below were pre- While the invention hasbeen described in detail and pared according to the process described inExample 1 with reference to specific embodiments thereof, it will or 2using the corresponding S-substituted 2-thi- 30 be apparent to oneskilled in the art that various oadenosine. Their physical propertiesand yields are changes and modifications can be made therein withalsoshown in Table 1. out departing from the spirit and scope thereof.

Table 1 Yield Product (9?) UV( .pH 1.6 X IO) R, Migration"2mHcxylthioadcnosinc-S'- 82 273 13.8 0.74 0.69 monophosphatc (Ba)2-n-Hcptylthioadcnosinc-S- 78 273 14.6 0.75 0.69 monophosphatc (Li,)2-n-Octylthioadcnoisinc-S'- 85 72 I39 078 0.69 monophsophatc (Ba)2-n-Nonylthioadcnosinc-5'- 85 273 14.8 0.84 0.68 monophosphate (Bu)2-n-Dcc lthiuadenosinc-S 75 272 13.6 0.85 0.67 monophosphatc (H) 2-(Z-EthyLn-hcxyl )thioadcnosinc-S -monophosphate 68 273 13.9 0.79 0.68(Bal 2(yelopcntylthioadcnosinc- 69 273 14.8 0.82 0.69 5-monophosphatc(Ba) 2-Cyclohcxylthioadcnosinc- 70 273 15.1 0.82 O. 70 5-mnnuphosphatclBa) 2Cyclohcxylmcthylthio adenosine -5'-monophosphate 68 272 14 8 0.830 72 Ball 2-p-Chlorobcnz ylthioadenosine-S'-monophosphatc 72 7 I36 0 9 0(Ba) 2-p-\'itrobcn?)lthioadcnusinc-5'-monophosphatc 78 274 22.0 0.86 065(Sal 2-trans-Crotylthioadcnosinc-S'-monophosphatc o) 273 1-4.2 0.70 0.72(Ba) 2-/3-melhallylthioadcnusinc- 5'-munophosphatc (Na-:1 53 273 13.80.69 0.72

R, \nluc in paper chromatography lsnlvent. npropzmollanimonia/watc|=20:10:3l "Migration In electrophoresis [pH 7.5.phosphate buffer. rel-.ltiw migration based onztdcnusinwi'-mnnoph0sphatel Elementary analysis of the above compoundswith 65 What is claimed is: respect to C. H. N and P showed goodconsistence with l. S-Substituted Z-thioadenosine-S '-monophosphates thecalculated values. represented by the following general formula NHZ NN)I N N RS HOPOCH OH OH and the alkali metal, alkaline earth metal andammonium salts thereof, wherein R is selected from the group consistingof a primary or secondary alkyl group having five to 10 carbon atoms, acycloalkyl group hav ing 5 to ID carbon atoms, a cycloalkylmethyl group,a benzyl group, a p-nitroor p-chlorobenzyl group, an allyl group and aB- or y-methallyl group.

2. 2-nHexylthioadenosine-5'-monophosphate and the alkali metal, alkalineearth metal and ammonium salts thereof of claim 1.

3. 2-n-Heptylthioadenosine-S-monophosphate and the alkali metal.alkaline earth metal and ammonium salts thereof of claim 1.

4. 2-n-Octylthioadenosine-S-monophosphate and the alkali metal, alkalineearth metal and ammonium salts thereof of claim 1.

5. Z-n-Nonylthioadenosine-S'-monophosphate and the alkali metal,alkaline earth metal and ammonium salts thereof of claim 1.

6. 2n-Decylthioadenosine-5'-monophosphate and the alkali metal, alkalineearth metal and ammonium salts thereof of claim 7. Z-( Z-Ethyl-n-hexyl)thioadenosine-S '-monophosphate and the alkali metal, alkaline earthmetal and ammonium salts thereof of claim 1.

8. Z-Cyclopentylthioadenosine-S'-monophosphate and the alkali metal.alkaline earth metal and ammonium salts thereof claim 1.

9. 2-Cyclohexylthioadenosine-S -monophosphate and the alkali metal.alkaline earth metal and ammonium salts thereof of claim 1.

l0. Z-Cyclohexylmethylthioadenosine-S -monophosphate and the alkalimetal, alkaline earth metal and ammonium salts thereof of claim 1.

ll. 2-p-Chlorobenzylthioadenosine-S '-monophosphate and the alkalimetal, alkaline earth metal and ammonium salts thereof of claim 1.

l2. 2-p-Nitrobenzylthioadenosi ne-S -monophosphate and the alkali metal,alkaline earth metal and ammonium salts thereof of claim 1.

l3. 2-trans-Crotylthioadenosine-S'-monophosphate and the alkali metal,alkaline earth metal and ammonium salts thereof of claim 1.

14. Z-B-Methallylthioadenosine-S'-monophosphate and the alkali metal,alkaline earth metal and ammonium salts thereof of claim 1.

l5. 2-n-Amylthioadenosine-5'-monophosphate and the alkali metal,alkaline earth metal and ammonium salts thereof of claim 1.

l6. 2-iso-Amylthioadenosine-5'-monophosphate and the alkali metal,alkaline earth metal and ammonium salts thereof of claim 1.

l7. 2-Allylthioadenosine-5'-monophosphate and the alkali metal, alkalineearth metal and ammonium salts thereof of claim 1.

l8. 2-Benzylthioadenosine-5'-monopl1osphate and the alkali metal,alkaline earth metal and ammonium salts thereof of claim I.

2. 2-n-Hexylthioadenosine-5''-monophosphate and the alkali metal,alkaline earth metal and ammonium salts thereof of claim
 1. 3.2-n-Heptylthioadenosine-5''-monophosphate and the alkali metal, alkalineearth metal and ammonium salts thereof of claim 4.2-n-Octylthioadenosine-5''-monophosphate and the alkali metal, alkalineearth metal and ammonium salts thereof of claim
 1. 5.2-n-Nonylthioadenosine-5''-monophosphate and the alkali metal, alkalineearth metal and ammonium salts thereof of claim
 1. 6.2n-Decylthioadenosine-5''-monophosphate and the alkali metal, alkalineearth metal and ammonium salts thereof of claim
 1. 7.2-(2-Ethyl-n-hexyl)thioadenosine-5''-monophosphate and the alkali metal,alkaline earth metal and ammonium salts thereof of claim
 1. 8.2-Cyclopentylthioadenosine-5''-monophosphate and the alkali metal,alkaline earth metal and ammonium salts thereof claim
 1. 9.2-Cyclohexylthioadenosine-5''-monophosphate and the alkali metal,alkaline earth metal and ammonium salts thereof of claim 10.2-Cyclohexylmethylthioadenosine-5''-monophosphate and the alkali metal,alkaline earth metal and ammonium salts thereof of claim
 1. 11.2-p-Chlorobenzylthioadenosine-5''-monophosphate and the alkali metal,alkaline earth metal and ammonium salts thereof of claim
 1. 12.2-p-NitrobenzylthioadenosinE-5''-monophosphate and the alkali metal,alkaline earth metal and ammonium salts thereof of claim 13.2-trans-Crotylthioadenosine-5''-monophosphate and the alkali metal,alkaline earth metal and ammonium salts thereof of claim
 14. 2- Beta-Methallylthioadenosine-5''-monophosphate and the alkali metal, alkalineearth metal and ammonium salts thereof of claim
 1. 15.2-n-Amylthioadenosine-5''-monophosphate and the alkali metal, alkalineearth metal and ammonium salts thereof of claim
 1. 16.2-iso-Amylthioadenosine-5''-monophosphate and the alkali metal, alkalineearth metal and ammonium salts thereof of claim 17.2-Allylthioadenosine-5''-monophosphate and the alkali metal, alkalineearth metal and ammonium salts thereof of claim
 1. 18.2-Benzylthioadenosine-5''-monophosphate and the alkali metal, alkalineearth metal and ammonium salts thereof of claim 1.